Neurotrophic factors are proteins which, inter alia, promote the survival of neurons and stimulate neurite growth (axonal and dendritic processes) and the synthesis of function-related neuronal enzymes. A number of factors have been isolated which have neurotrophic activities, including nerve growth factor (NGF) and fibroblast growth factors.
Beginning in the late 1970's, "ciliary neurotrophic factors" (CNTFs) were described and preliminarily characterized. CNTF was originally identified as a factor which is specifically required for the survival of one population of neurons, the chick embryo cholinergic parasympathetic motor neurons of the ciliary ganglion. CNTF is also able to support certain NGF-responsive neurons. Chick eye CNTF was shown to be a 20.4 kD protein with an isoelectric point of 5.0 which supported the survival not only of ciliary ganglion neurons but also cultured avian and mammalian sensory neurons and avian sympathetic neurons (Adler and Varon, Brain Res. (1980) 188:437-448; Landa et al., Dev. Biol. (1980) 74:401-408; Manthorpe et al., J. Neurochem (1980) 34:69-75); Barbin et al., J. Neurochem. (1984) 43:1468-1478; Manthorpe et al., J. Neurochem. (1982) 38:225-242).
Partially purified CNTF was isolated from rat sciatic nerves and shown to have a specific activity of 2.times.10.sup.7 trophic units (TU) per mg. (Manthorpe et al., Brain Res. (1986) 367:282-286). Homogeneous CNTF was subsequently obtained from rat sciatic nerves (PCT Application No. PCT/US90/01390). The obtainment of sequenceably pure CNTF made it possible to isolate DNA sequences encoding mammalian CNTFs, including rat, rabbit and human CNTF (Stockli et al., Nature (1989) 342:920-923; European Patent Application No. 0 385 060; Lam et al., Gene in press) and to deduce their complete amino acid sequences. Human CNTF has been determined to be a protein 200 amino acids in length.